Although amyloid precursor protein (APP) is ubiquitously expressed, much of the focus on APP biology with respect to Alzheimer's disease (AD) has focused on the brain due to high levels of neuronal expression. However, the enteric nervous system of the gastrointestinal tract also expresses APP. Moreover, the gastrointestinal tract is filled with a plethora of immune cell types that broadly affect not only the function of te gut but also other organ systems including the brain. Recognition of this comparison forces one to consider whether or not A aggregation/deposition with subsequent inflammation characteristic of the brain during AD occurs in parallel in the digestive tract. This suggests an opportunity for peripherally monitoring APP-related biology or therapeutic interventions as well as a novel understanding of the pathophysiology of AD. Even more exciting is the possibility that the two organ systems influence disease phenotype in one another based upon not only immune cell interactions but also the direct autonomic innervation of the gastrointestinal tract. Our preliminary data using a transgenic mouse model of AD demonstrated increased APP levels, A deposition and immune dysfunction in the intestines similar to findings from brains. Moreover, manipulation of the peripheral immune system with therapeutic antibodies was sufficient to attenuate brain microgliosis in these mice. Most importantly, we observed APP immunoreactivity, A plaques, and phospho-tau containing tangles in AD large intestines validating the relevance of the mouse model. In comparison to human diseased intestines, we will continue using the most relevant mouse models of AD to define the temporal relationship between brain and gastrointestinal disease identifying both neuronal and immune changes in correlation with both memory performance and gut function. We will also determine the specific role of APP and its metabolites in regulating both intestinal epithelial and immune cell phenotypes. Finally, by altering gut-brain communication we will determine whether it is possible to regulate disease progression in either organ by manipulating immune or nervous communication.